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Diverse genetic abnormalities lead to NF-κB activation in multiple myeloma

Two new studies may lead to the development of more effective therapies for individuals with multiple myeloma (MM), a common and incurable blood cell cancer. The research, published by Cell Press in the August issue of the journal Cancer Cell, provides new insight into the molecular mechanisms that underlie aberrant NF-κB activity in MM tumor cells and underscores the relevance of the NF-κB signaling pathway as a target for MM therapy.

MM is a cancer of the plasma cell, a blood cell that produces antibodies to help the body fight off infections. Previous research implicates abnormal activation of the NF-κB signaling pathway as a key event in MM pathology. NF-κB target genes are known to be involved in cell proliferation and cell survival. Although there is significant overlap and interplay between them, there are two separate pathways that lead to activation of NF-κB, the classical pathway and the alternative pathway.

Constitutive activation of NF-κB to block apoptosis has been implicated in various types of cancer, but the molecular mechanisms involved are not well understood. Two separate research groups used a variety of sophisticated genomic techniques to examine mutations in hundreds of MM patient samples and cell lines to identify mutations that impact NF-κB activation.

Dr. Louis M. Staudt from the National Cancer Institute led a research group who revealed the importance of both the classical and alternative NF-κB pathways in MM pathogenesis. Most MM patient samples examined exhibited NF-κB pathway activation via diverse genetic abnormalities. Importantly, targeted disruption of the classical NF-κB signaling blocked myeloma proliferation and induced cell death. These genetic and functional data provide a molecular framework for the rational development of NF-κB pathway inhibitors for the therapy of MM, offers Dr. Staudt.

In a separate study, Dr. Rafael Fonseca, from the Mayo Clinic Arizona, and colleagues report mutations in several genes that result in constitutive activation of the alternative NF-κB pathway. We propose that the acquisition of the mutations identified in our study results in the accumulation of malignant plasma cells beyond the physiological control of the bone marrow compartment. Our results suggest a mechanism by which MM cells can overcome these limitations through acquisition of mutations that result in constitutive and ligand-independent activation of the alternative NF-κB pathway, explains Dr. Fonseca.

Taken together, results for these studies define diverse mutations that lead to pathological activation of NF-κB signaling in MM and describe a shift of plasma cells from dependence on the microenvironment to an environment-independent state during progression of MM. Regardless of the specific method of activation, the NF-κB pathway plays a central role in MM pathogenesis and is an excellent target for development of new therapeutics.

Contact: Erin Doonan
Cell Press

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